tbuckley/cabot-search huggingface dataset:
Single-agent anti-PD-1 or combined with ipilimumab in patients with mucosal melanoma: an international, retrospective, cohort study
Authors: F. Dimitriou, K. Namikawa, I.L.M. Reijers, E.I. Buchbinder, J.A. Soon, A. Zaremba, P. Teterycz, M.J. Mooradian, E. Armstrong, Y. Nakamura, M.G. Vitale, L.E. Tran, X. Bai, C. Allayous, S. Provent-Roy, A. Indini, P. Bhave, M. Farid, K.C. Kähler, I. Mehmi, V. Atkinson, O. Klein, C.J. Stonesifer, F. Zaman, A. Haydon, R.D. Carvajal, O. Hamid, R. Dummer, A. Hauschild, M.S. Carlino, M. Mandala, C. Robert, C. Lebbe, J. Guo, D.B. Johnson, P.A. Ascierto, A.N. Shoushtari, R.J. Sullivan, B. Cybulska-Stopa, P. Rutkowski, L. Zimmer, S. Sandhu, C.U. Blank, S.N. Lo, A.M. Menzies, G.V. Long
Journal: Annals of Oncology (2022)
Abstract 84: Sensitive and unbiased detection of clinically actionable gene fusions from FFPE tumor biopsies using the Arima-HiC platform
Authors: David Jacob Hermel, Kristin Sikkink, Derek Reid, Anthony Schmitt, Darren S. Sigal
Journal: Cancer Research (2022)

Abstract Accurate and sensitive identification of gene fusions is critical to understanding disease mechanisms and the development and selection of optimal treatment regimens for cancer patients. Typically, these fusions are detected using low-resolution karyotyping, low throughput and biased FISH assays, or RNA sequencing approaches; however, the accuracy and sensitivity of gene fusion detection can be limited by factors such as low transcript abundance, transcript length, RNA degradation from formalin fixed paraffin embedded (FFPE) tissues, or the limited availability of fresh biopsy samples for RNA extraction. To address these limitations, we developed a novel approach to identifying gene fusions from FFPE samples using the Arima-HiC platform and short-read sequencing. We performed pan-cancer analysis on 12 FFPE adult tumor biopsies, each with gene fusions known to be clinically actionable. With this newly developed Hi-C workflow we identified all the known gene fusions with 100% sensitivity in the samples including those involving ALK, NTRK3, ROS1, FGFR2, and SS18 genes. This approach also revealed that the NTRK3 gene fusion was the result of a more complex rearrangement within chr12, within chr15, and between chr12 and chr15. Additionally, we detected the presence of numerous structural variants per sample in addition to the known gene fusion in each sample. For example in a bile duct tumor, Arima-HiC detected an FGFR2-EEA1 gene fusion, as well as 25 other structural variants genome-wide including in a CPD-LASP1 gene fusion This gene fusion has not been reported to our knowledge, however, LASP1 is a reported 3’ fusion partner with MLL in leukemia. While these findings are not clinically actionable today, the unbiased, accurate, and sensitive detection of structural variants from frozen and FFPE solid tumor biopsies may facilitate further research into their relationship between disease mechanisms and clinical outcomes. Taken together, these findings demonstrate the analytical utility of Arima Hi-C sequencing technology to provide both chromosome-scale and gene-level resolution for the detection of structural variants in tumor biopsies samples. This workflow can provide improved access to critical genomic information from FFPE blocks for the identification of pathognomonic and druggable gene fusion events and other structural variants across tumor types. Citation Format: David Jacob Hermel, Kristin Sikkink, Derek Reid, Anthony Schmitt, Darren S. Sigal. Sensitive and unbiased detection of clinically actionable gene fusions from FFPE tumor biopsies using the Arima-HiC platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 84.
Abstract 5623: CD137 humanized mice for preclinical efficacy evaluation of therapeutic antibodies
Authors: Yunlong Jiang, Tingting Gu, Weiwei Yu, Hongyan Sun, Mingkun Zhang, Juan Liang, Shuai Li, Cunxiang Ju, Jing Zhao, Xiang Gao, Mark W. Moore
Journal: Cancer Research (2022)

Abstract CD137 (41-BB, tumor necrosis factor receptor superfamily 9), expressed on activated T cells and NK cells, has gained increased attention as an anti-tumor target because of remarkable clinical efficacy using either a single agent or in combination with other immune checkpoint inhibitors. We constructed CD137 humanized mice based on two different backgrounds, C57BL6 and BALB/c mice, as well as dual-target and triple-target mice crossbred with PD1/PDL1 humanized mice to create an ideal model to study CD137 target drugs. The normal immune cell population in peripheral blood were not affected in CD137 humanized mice, and hCD137 was expressed on T cells after the stimulation with a anti CD3 antibody. We verified the efficacy of anti-CD137 drugs in BALB/c-hCD137 mice inoculated with different cancer cell lines (i.e. CT26, EMT6 and 4T1). The drug Urelumab showed a dramatic response in the hCD137 mice model inoculated with CT26 and EMT6 but not with 4T1 cell line. In a rechallenge study, no tumors grew in tumor-free mice previously treated with Urelumab, with effector memory T cells increased in peripheral blood, indicating Urelumab has a relatively long-lasting anti-tumor effect. The combination of Urelumab and anti-PD1 has a stronger tumor growth inhibition effect than that of anti-CD137 or anti-PD1 monotherapy on dual-target or triple target mice. These data show that the humanized CD137 mouse is a suitable model for evaluating the monotherapies or combination therapies targeting CD137. Citation Format: Yunlong Jiang, Tingting Gu, Weiwei Yu, Hongyan Sun, Mingkun Zhang, Juan Liang, Shuai Li, Cunxiang Ju, Jing Zhao, Xiang Gao, Mark W. Moore. CD137 humanized mice for preclinical efficacy evaluation of therapeutic antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5623.
Abstract 2706: Ultra-Low Input High-Fidelity (ULI-HiFi) long-reads uncover variants in genomic dark matter from pre-cancer polyp and tumor samples
Authors: Hayan Lee, Graham Erwin, Aaron Horning, Raushun Kirtikar, Emmett Griffin-Baldwin, William Rowell, Philip Li, Sarah Kingan, Michael P. Snyder
Journal: Cancer Research (2022)

Abstract Long-read sequencing technologies have been constrained by high error rates and large sample input requirements. The recent introduction of HiFi sequencing has enabled highly accurate detection of single-nucleotide variants (SNVs) from long reads (10-15 kb). However, a major limiting factor is the amount of sample input required, where current protocols require ≥15 micrograms of DNA. Here we report Ultra-Low Input High Fidelity Sequencing (ULI-HiFi), an amplification-based library preparation that reduces this input to 10 nanograms of DNA, a more than 10,000-fold reduction in sample input. When the ultra-low input method was tested using a benchmark genome, HG002, we observed high precision and improved recall of structural variants compared to a ground truth dataset from the Genome in a Bottle Consortium. We also benchmarked small variants and reported the accurate analysis of many variants in clinically important genes that are unmappable with short reads. We used this strategy to sequence tumor and polyp samples from a patient with familial adenomatous polyposis, a hereditary form of colon cancer, which revealed SNVs and structural variants not detected by short-read techniques. This strategy will enable the improved characterization of genetic variants from limited clinical samples. Citation Format: Hayan Lee, Graham Erwin, Aaron Horning, Raushun Kirtikar, Emmett Griffin-Baldwin, William Rowell, Philip Li, Sarah Kingan, Michael P. Snyder. Ultra-Low Input High-Fidelity (ULI-HiFi) long-reads uncover variants in genomic dark matter from pre-cancer polyp and tumor samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2706.
Abstract 2894: QL401, a dual PD-L1/CD47 blocker effective against both solid and hematological malignancies with improved blood safety
Authors: Irene Tang, Lauren Schwimmer, Shenda Gu, Wei Wei Prior, Hieu V. Tran, Allan Chan, Anna McClain, Shihao Chen, Chuanzeng Cao, Chunyan Sun, Meimei Si, Guijiang Wang
Journal: Cancer Research (2022)

Abstract Upregulation of CD47, a “Do Not Eat Me” signal, is observed in nearly all solid and hematological malignancies. Engagement of CD47 on tumor cells with SIRPα on macrophages inhibits phagocytosis of tumor cells. Anti-CD47 antibodies block the CD47 - SIRPα engagement and reactivate phagocytosis of tumor cells by macrophages. Yet the ubiquitous expression of CD47 on normal cells, including red blood cells, presents a therapeutic challenge. Systemic targeting of CD47, by either anti-CD47 monoclonal antibodies or SIRPα-Fc fusion proteins, yielded only moderate clinical benefit due to severe adverse side effects, mainly anemia. QL401 is PD-L1 x CD47 bispecific antibody engineered to reduce binding to red blood cells while retaining potent phagocytic activation of macrophages in vitro and delayed tumor growth in vivo. QL401 comprises three functional components: a PD-L1 binding Fab arm, a CD47 binding scFv arm, and a human IgG4 backbone. The PD-L1 binding arm provides both tumor targeting and blocking of PD-1 for reactivating T cells. The CD47 arm blocks the binding of SIRPα, the “Do Not Eat Me” signal, while the IgG4 Fc retains Fc gamma receptor binding to provide a phagocytic “Eat Me” signal. Therefore, QL401 is multi-functional antibody that re-actives both the innate and adaptive immune response. In preclinical efficacy studies, QL401 potently blocked SIRPα to promote phagocytosis of tumor cells with sub-nanomolar potency. In vivo efficacy studies in mouse models of solid and hematological tumors showed QL401 to be comparable or superior to PD-L1 or CD47 monoclonal antibodies alone and in combination. In vitro safety evaluation of Q401 showed significantly reduced binding and phagocytosis of red blood cells, in contrast to CD47 monoclonal antibodies. In addition, Q401 did not induce hemagglutination. In non-human primates, QL401 was well tolerated up to 100 mg/kg without reduction of red blood cells below normal range. A phase 1 dose escalation and expansion study is expected to start Q1 2022 to evaluate the safety, tolerability, and early efficacy of QL401. Citation Format: Irene Tang, Lauren Schwimmer, Shenda Gu, Wei Wei Prior, Hieu V. Tran, Allan Chan, Anna McClain, Shihao Chen, Chuanzeng Cao, Chunyan Sun, Meimei Si, Guijiang Wang. QL401, a dual PD-L1/CD47 blocker effective against both solid and hematological malignancies with improved blood safety [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2894.
The Reversible Fourth-Generation EGFR Tyrosine Kinase Inhibitor OBX02–011 Overcomes C797S-Mediated Resistance in Lung Cancer
Authors: Yun Jung Choi, Da-Som Kim, Young Hoon Sung, Dong Ha Kim, Kyungtaek Im, Hyeonjeong Lee, Chae Won Lee, Jeongin Cho, Joongkee Min, Dong-Cheol Woo, Sung-Eun Kim, Sunho Lee, Yun Jeong Kong, Hyung Chul Ryu, Jae-Sun Kim, Rajesh Rengasamy, Wonjun Ji, Chang-Min Choi, Jae Cheol Lee, Jin Kyung Rho
Journal: Cancer Research (2022)

Abstract Osimertinib is an irreversible third-generation EGFR tyrosine kinase inhibitor (TKI) that was initially developed to overcome the EGFR T790M mutation and is used as a standard therapy in patients with advanced non–small cell lung cancer (NSCLC) with EGFR-activating mutations. Despite the remarkable initial efficacy, osimertinib, like other EGFR-TKIs, is limited by the emergence of acquired resistance. As the EGFR mutation C797S has been identified as a key driver of acquired resistance to osimertinib, development of a drug that targets this clinically relevant mutation could help improve patient outcomes. Here, we report the discovery and preclinical efficacy of OBX02–011, a reversible fourth-generation EGFR-TKI that overcomes the EGFR C797S mutation. Compared with approved EGFR-TKIs, OBX02–011 showed potent anticancer effects and inhibited EGFR-related signaling in various models, including those harboring the EGFR C797S mutation. In addition, in transgenic mouse models (EGFRL858R/T790M/C797S), OBX02–011 treatment effectively inhibited tumor growth and EGFR activity, leading to enhanced survival. Collectively, these results suggest that OBX02–011 may be a promising new EGFR-TKI to overcome C797S-mediated resistance in NSCLC. Significance: OBX02–011 is designed to target EGFR C797S and can overcome EGFR double and triple mutations to effectively treat lung cancer.
Abstract 405: A new mechanism of drug resistance in cancer: extracellular ATP-induced resistance by macropinocytosis-mediated internalization and redox changes
Authors: Haiyun Zhang, Xiaozhuo Chen
Journal: Cancer Research (2022)

Abstract Drug resistance are responsible for most relapses and up to 90% of cancer related death. The opportunistic uptake of extracellular molecules has been named as a key emerging hallmark of cancer metabolism. In tumor microenvironment, intratumoral extracellular ATP (eATP) levels are 1,000 times or more higher than those in corresponding normal tissues. Our previous studies have shown that eATP can be taken up by cancer cell via macropinocytosis, leading to substantial increase in intracellular ATP levels. We found that this high intracellular ATP levels contribute to drug resistance in several ways: first, it directly fueled and enhanced drug-pumping activity of major ATP-binding cassette (ABC) multidrug transporters, which are located in plasma membrane and can pump out a wide range of substrates including anticancer drugs, leading to reduced intracellular drug retention. Secondly, ATP treatment upregulated gene expression of the major ABC transporters, and this gene regulatory effect of ATP was comparable to TGF-beta, which is a well-established epithelial-mesenchymal transition (EMT) inducer, and EMT is known to induce ABC transporter expression and drug resistance. Moreover, eATP treatment led to an increase in intracellular glutathione (GSH) levels, probably by enhancing GSH synthesis. Increased GSH levels have been described to significantly contribute to drug resistance. We also found eATP altered cellular redox state, which potentially stimulates EMT. Furthermore, we performed RNA-sequencing and identified several genes that may serve as downstream factors of eATP in promoting EMT and drug resistance. We are currently investigating the roles of these genes by knocking down gene expression or knocking out these genes. Citation Format: Haiyun Zhang, Xiaozhuo Chen. A new mechanism of drug resistance in cancer: extracellular ATP-induced resistance by macropinocytosis-mediated internalization and redox changes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 405.
Abstract 4068: The potent quadruplex-binding compound SOP1812 shows potent anti-proliferative activity in a prostate cancer cell panel and anti-tumor activity in an <i>in vivo</i> model of metastatic prostate cancer
Authors: Nicole Williams, Jenny Worthington, Stephen Neidle, Ahmed Ahmed
Journal: Cancer Research (2022)

Abstract The compound SOP1812, a tetra-substituted naphthalene diimide (ND) derivative has been designed as a potent compound for targeting quadruplex sequences in cancer genes. It has been previously disclosed to have single-digit nM anti-proliferative activity in a panel of human cancer cell lines (Ahmed et al., ACS Med Chem Lett, 2020, 11, 1634-1644). It also has significant anti-tumor activity in several models for pancreatic cancer. We have also previously shown that two early-generation ND derivatives are active in both androgen-positive and negative prostate cancer cell lines (Mitchell et al, Biochemistry, 2013, 32, 1429-1436) and that these compounds down-regulate the transcription of quadruplex-containing genes such as c-MYC. We now report that this compound also shows significant anti-proliferative activity in several prostate cancer cell lines, notably with a GI50 value of 3 nM in the PC3 cell line. Abiraterone has a GI50 in this line of 4820 nM. By contrast SOP1812 has a GI50 of 247 nM in the LNCaP line, which is also derived from a patient with metastatic prostate cancer but is androgen positive. The PC3 line is derived from a metastatic carcinoma following androgen suppression therapy and is thus androgen independent and is a model for castration-resistant prostate cancer when hormone therapies are no longer effective. We have evaluated the activity of SOP1812 in the PC3 xenograft model using a twice-weekly 1 mg/kg dose regimen IV administered, against a saline control and abiraterone, at a daily dose of 200 mg/kg, administered by the PO route, both over a 28-day period. No weight loss was observed in treated animals with either drug. SOP1812 produced statistically significant tumor shrinkage (P value of 0.0008) relative to the controls, with a T/C value of 33.5% on day 28. Abiraterone treatment resulted in a T/C value of 61.6%, with a P value of 0.0382. SOP1812 is bio-available at therapeutic doses and is well tolerated at these levels in this animal model. It is currently being evaluated as a candidate for clinical development by Qualigen Therapeutics Inc. Citation Format: Nicole Williams, Jenny Worthington, Stephen Neidle, Ahmed Ahmed. The potent quadruplex-binding compound SOP1812 shows potent anti-proliferative activity in a prostate cancer cell panel and anti-tumor activity in an in vivo model of metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4068.
Abstract 2344: BRAF inhibitor resistant thyroid cancer cells exhibit altered cellular energetics
Authors: Eric Bolf, Rebecca Schweppe
Journal: Cancer Research (2022)

Abstract Thyroid cancer is the most commonly diagnosed endocrine malignancy. Although prognosis for patients is positive overall, dedifferentiated thyroid tumors and invasive thyroid tumors are difficult to treat. There is one FDA approved targeted therapy in use for in BRAF mutant, highly dedifferentiated anaplastic thyroid cancer, a combination of the BRAF inhibitor dabrafenib and the ERK inhibitor trametinib. While this treatment improves outcomes, resistance is of great concern. In other cancers driven by BRAF mutations, particularly melanoma, a known driver of BRAF inhibitor resistance is enhanced oxidative phosphorylation. We therefore investigated the energetics of thyroid cancer cells to determine whether metabolic changes can drive resistance in thyroid cancer. We have previously determined sensitivity to dabrafenib by area under the curve to classify cell lines as sensitive or resistant (Hicks HM et al, 2021). We used CUTC5 cells as our primary model of intrinsically sensitive cells and CUTC60 cells to model intrinsic resistance. We observed both cell lines had similar basal oxygen consumption rates (OCR), however dabrafenib treatment reduced this in the sensitive CUTC5 cells and did not in the resistant CUTC60 cells. Additionally, maximum OCR was reduced in the CUTC5 cells with as little as 10 nM dabrafenib. In a preliminary experiment, CUTC60 cells were co-treated with dabrafenib and rotenone, an inhibitor of the electron transport chain, and synergistic inhibition of proliferation was observed. We further investigated energetics in the dabrafenib sensitive cell line KTC1 and KTC1-VA7, which are derived from KTC1 and BRAF-inhibitor resistant (Danysh BP et al, 2016). Unlike the other cells evaluated these cells did not have spare respiratory capacity. Additionally, dabrafenib treatment did not alter basal OCR except at the highest doses. Although, we did observe a reduction in glycolysis in the parental KTC1 upon dabrafenib treatment, which was not observed in the KTC1-VA7 cells. Sensitive CUTC5 cells also exhibited a greater decrease in glycolysis than resistant CUTC60 cells. From this, we conclude that glycolysis may contribute to dabrafenib resistance and merits further investigation. With regards to oxidative metabolism, we only observed a reduction in OCR in a dabrafenib sensitive cell line and there was synergistic inhibition in the resistant CUTC60 cells treated with both dabrafenib and rotenone, suggesting that oxidative metabolism aids the cells in tolerating BRAF inhibition. Further screening of dabrafenib sensitive and resistant cells is necessary to determine if this is a function of dabrafenib sensitivity. Citation Format: Eric Bolf, Rebecca Schweppe. BRAF inhibitor resistant thyroid cancer cells exhibit altered cellular energetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2344.
Abstract 4212: <i>In situ</i>vaccination with <i>Flt3l</i> gene-modified CD103+type 1 conventional dendritic cells (cDC1) in murine models of non-small cell lung cancer (NSCLC)
Authors: Jensen W. Abascal, Raymond J. Lim, Ramin Salehi-Rad, Zhe Jing, William P. Crosson, Bitta P. Kahangi, Edgar Perez Reyes, Diana Reyimjan, Jessie Zhu, Linh M. Tran, Manash Paul, Kostyantyn Krysan, Bin Liu, Steven M. Dubinett
Journal: Cancer Research (2022)

Abstract A major hurdle in treatment of Non-Small Cell Lung Cancer (NSCLC) with anti-PD-1 immune checkpoint blockade (ICB) therapy is a lack of response (primary resistance) and relapse after an initial response (acquired resistance). Recent studies reveal that responses to PD-1/PD-L1 blockade are associated with high tumor mutational burden (TMB), increased CD8+ T cell infiltration and high baseline PD-L1 expression within the tumor microenvironment (TME), while impaired tumor antigen presentation and the immunosuppressive TME have been associated with resistance to ICB. One approach to overcome anti-PD-1 resistance is to intratumorally vaccinate NSCLC tumors with gene modified conventional dendritic cells (cDC), specifically the type I conventional DC (cDC1) lineage. Recent studies have established that generation of an anti-tumor immune response driven by CD8+ T cells requires the cross presentation of tumor associated antigens and that cDC1s are the primary cross presenting APC subtype in vivo, which can license CD8+ T cells to initiate an adaptive anti-tumor immune response. In addition, previous studies have shown that intratumoral administration of the FMS-like tyrosine kinase 3 ligand (FLT3L) protein can expand endogenous CD103+ cDC1 cells in the TME and augment anti-tumor immune responses to ICB therapy. Here, we engineered murine CD103+ cDC1 cells to constitutively secrete soluble FLT3L (FLT3L_cDC1) and performed in situ vaccination studies on anti-PD1 resistant murine models of NSCLC with LKB1-deficiency and elevated TMB that better represents human disease. The FLT3L_cDC1 cells showed enhanced anti-tumor efficacy compared to non-modified cDC1 cells and synergized with anti-PD-1 ICB to inhibit tumor growth. Our data suggests intratumoral injection of FLT3L_cDC1 cells may represent a promising strategy to potentiate the efficacy of ICB and improve outcomes for patients with primary resistance PD-1/PD-L1 monotherapy. *B. Liu and S.M Dubinett contributed equally to this work Citation Format: Jensen W. Abascal, Raymond J. Lim, Ramin Salehi-Rad, Zhe Jing, William P. Crosson, Bitta P. Kahangi, Edgar Perez Reyes, Diana Reyimjan, Jessie Zhu, Linh M. Tran, Manash Paul, Kostyantyn Krysan, Bin Liu, Steven M. Dubinett. In situvaccination with Flt3l gene-modified CD103+type 1 conventional dendritic cells (cDC1) in murine models of non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4212.